The T cell costimulatory receptor, OX40, also known as CD134, TNFRSF4 and ACT35, is a member of the tumor necrosis factor receptor superfamily. It is involved in potentiating T cell responses triggered through TCRs, and expressed primarily on activated T cells, including CD4+ T cells, CD8+ T cells and regulatory T-cells (Tregs) (Redmond et al., (2009) Crit. Rev. Immunol. 29(3): 187-201; Jensen et al., (2010) Semin. Oncol. 37(5):524-532). Unlike CD 28, OX40 is not expressed on naïve T cells. Its expression peaks between 12 hours and 5-6 days post antigen stimulation. Its ligand OX40L, in a similar manner, is induced and detected on the surface of antigen presenting cells 1 to 3 days after antigen encounter (Willoughby et al., (2017) Mol Immunol 83: 13-22).
Upon binding to OX40L, OX40 signaling was reported to increase cytokine production and enhance CD4+ and CD8+ T cell proliferation and survival (Weinberg et al., (1998), Semin Immunol 10(6): 471-480; Kjaergaard et al., (2000) Cancer Res 60(19): 5514-5521; Willoughby et al., supra; Croft et al., (2003) Cytokine Growth Factor Rev. 14 (3-4):265-273). In vivo studies showed that OX40 receptor engagement by OX40L improved tumor-free survival in mice bearing tumors such as lymphoma, melanoma, sarcoma, colon cancer, breast cancer and glioma ((Aspeslagh et al., (2016) Eur J Cancer 52: 50-66; Bell et al. (2016) Oral Oncol 52: 1-10; Webb et al., (2016) Clin Rev Allergy Immunol 50(3): 312-332; Willoughby et al., supra).
OX40 also plays an important role in Treg development and function. OX40 signaling in some contexts boosted Treg fitness and proliferation, and OX40+ Tregs were found at tumor sites at higher levels (Piconese et al., (2014) Hepatology 60(5):1494-1507; Ruby et al., (2009) J Immunol 183: 4853-4857; Piconese et al., (2010) Eur J Immunol 40: 2902-2913). However, high doses of agonistic anti-OX40 antibodies were shown to successfully block Treg mediated suppression by reducing Treg viability via an apparently apoptotic process (Voo et al., (2013) Immunol. 191 (7): 3641-3650).
With its role in immune response as described above, OX40 has been identified as a potential target for immunotherapy. Agonistic anti-OX40 antibodies that activate OX40 signaling have been used in preclinical studies to treat tumors and infectious diseases (Boettler et al., (2012) PLoS Pathog. 8(9): e1002913; Jahan et al., (2018) Neuro Oncol. 10; 20(1):44-54), while antagonistic antibodies which block OX40 signaling may be used to treat autoimmune or inflammatory diseases. In a first-in-human phase I clinical trial using a murine IgG1, anti-OX40 monoclonal agonistic antibody, 12 out of 30 patients having metastatic solid malignancies showed evidence of tumor regression after just one cycle of treatment (Curti et al. (2013) Cancer Res 73(24): 7189-7198). Anti-OX40 monotherapy has been further studied in combination with other monoclonal antibodies, chemotherapy and cytokines to improve therapeutic effects (Linch, McNamara et al. (2015) Front Oncol 5: 34; Colombo et al., (2017), Clin Cancer Res 23(20): 5999-6001; Foote et al., (2017) Cancer Immunol Res 5(6): 468-479).
Despite the insight into the structural basis of the OX40-OX40L interaction, what determines whether an antibody is an agonistic or antagonistic antibody against OX40 is not yet clear. There remains a need for more OX40 antibodies with desirable pharmaceutical characteristics.